10-alkyl steroids and processes for their preparation



United States Patent 3,309,386 IO-ALKYL STEROIDS AND PROCESSES FOR 7THEIR PREPARATION Arthur Boller, Binningen, and Andor Fiirst and ErnstGerhard Herzog, Basel, Switzerland, assignors to Holiruann-La RocheInc., Nutley, N.J., a corporation of New Jersey No Drawng. Filed Feb.18, 1965, Ser. No. 433,774 Claims priority, application Sggitzerland,May 9, 1962,

7 Claims. (Cl. 260397.3)

This application is a continuation-in-part of application Ser. No.277,007, filed Apr. 30, 1963, now abandoned. The present inventionrelates to novel steroids and to processes for their preparation. Moreparticularly, the present invention relates to steroids having theformula I OH-Ra wherein R R and R are hydrogen or lower alkyl, e.g.,methyl, ethyl, propyl, isopropyl, butyl, etc., and R, is

O H 0R5 R 0 lower alkyl ll R ii C-R I 3 CH2 R wherein R through R havethe meanings given above and R, is selected from the group consisting ofO H 0 R R 0 lower alkyl ll R50 lower alkenyl R5O\ lower alkinyl C and Cum carbonate or on barium carbonate. This hydrogena tion reaction alsoresults in the formation of the 1,2,4,5-

Patented Mar. 14, 1967 "ice tetrahydro-derivatives of the compounds ofFormula I, i.e., in compounds having the formula A compound of theformula R Ra 19-vinyl-androsta-l,4-dien-3,17-dionel9-vinyl-androsta-1,4-dien-3-on-l7-ol 19-vinyl l7-methyl-androsta-1,4-dien-3-on-l7-ol19-vinyl-17-ethinyl-androsta-1,4-dien-3-on-17-ol19-vinyl-17-ethenyl-androsta-1,4-dien-3-on-l7ol19-vinyl-17-ethy1-androsta-1,4-dien-3-on-17 -0119-vinyl-17-allyl-androsta-1,4-dien-3-on-17-01 The IO-alkyl steroids ofFormula I, Ia, and 112 exhibit antigonadotropic activity; in particular,inhibition of prostatic growth. They are useful asgonadotropin-inhi-biting agents.

Example 1 3 g. of 19-vinyl-androsta-l,4-dien-3,17-dione is dissolved in10 m1. of absolute thiophene-free benzene and 40 ml. of n-hexane isadded thereto. To this solution is added 1 g. of palladium-calciumcarbonate catalyst and hydrogenation carried out at room temperature andnormal pressure until about 1.1 moles of hydrogen are taken up. Thecatalyst is filtered off and the solvent removed under vacuum. 3 g. of ayellow oil is obtained, which crystallizes almost completely. 2 g, ofthese crystals are dissolved in high boiling petroleum ether andchromatographed on 60 g. of aluminium oxide (activity III). By elutionwith a mixture of petroleum ether (boiling point 40-45 C.) and benzene(8:1), mg. of l9-ethyl-androstan-3,l7-dione is obtained, which afterrecrystallization from ether-petroleum ether melts at 124-125" C.

By elution with benzene, there is obtained 1 g. of 19-ethyl-androsta-l,4-dien-3,l7-dione, which after recrystallization fromether-petroleum ether melts at C.

Example 2 Following the precess of Example 1, l9-vinyl-androsta-1,4-dien-3-on-l7-ol is converted into 19-ethyl-androsta-1,4-dien-3-on-l7-ol, melting point 149150 C. (from ether-petroleumether).

Example 3 Following the process of Example 1,19-vinyl-17otmethyl-androsta-1,4-dien-3-on-17B-ol is converted into 19-ethyl-l7ot-rnethyl-androsta-1,4-dien-3 on-17 ol; melting point 135-136"C.

Exwm ple 4 100 mg. of finely divided lithium metal is added to 150 ml.of liquid ammonia under stirring. After a short time the expected darkblue color appears. After stirring for an additional 2 minutes there isaddied thereto all at once a solution of 620 mg. of19-ethyl-androsta-1,4-dien- 3,17-dione in 25 mg. of absolutetetra-hydrofuran and the mixture stirred for 2% minutes. As soon as theaddition begins, the blue color becomes lighter. However, the colorremains during the entire reaction period. After 2% minutes, 5 g. ofpulverized ammonium chloride is added all at once, and the reactionmixture becomes completely decolorized. The ammonia is then removed andthe residue taken up in water-ether. The aqueous portion is extractedthree times with ether, the other extracts combined with the above etherlayer, dried, and the ether removed by evaporation, leaving 606 mg. of abright yellow oil. This oil is dissolved in benzenepetroleum ether (1:1)and added to a thirty-fold quantity of aluminium oxide of activity III.This same solvent mixture is then used to elute from the column 203 mg.of a colorless oil, which crystallizes upon standing. After onerecrystallization from ether-petroleum ether, the product, 19-ethyl-A-androstene-3,l7-dione, is analytically pure; melting point 144-145 C.;yield 126 mg.

Example 5 According to the process of Example 4, l9-ethyl-Aandrosten-3-on-17-ol is obtained from 19-ethyl-androsta-1,4-dien-3-on-17-ol; melting point of the product 152 C. (fromether-petroleum ether).

Example 6 200 mg. of 19-ethyl-androsta-1,4-dien-3-on-17-ol (prepared asdescribed in Example 2) is dissolved in 4 m1. of absolute pyridine and 1ml. of propionic acid anhydride. The solution is allowed to stand atroom temperature for 24 hours, then poured out into water and extractedwith ether. The ethereal portion is washed with aqueous oxalic acid,sodium carbonate solution and water. After drying over anhydrous sodiumsulfate, the solvent is removed and the oily residue (257 mg.) ischromatographed on silica-gel. By elution with benzene-ether (5:1) thereis obtained 217 mg. of light yellow oily 19-ethyl-androsta-1,4-dien-3-on-17-ol-17-propionate which crystallized on standing afterfour weeks. U.V.: s =14,600; I.R.: (fluid) 5.80/L, 8.53m ester; 6.056.18 625 ring A- dienone.

We claim:

1. A compound selected from the group consisting of (a) a compound ofthe formula E CH7 CH3 CH2 R 4 wherein R is selected from the groupconsisting of (H) H\ /OR R50 lower alkyl C C and C wherein R is selectedfrom the group consisting of hydrogen and lower alkanoyl.

2. A 1,2,4,S-tetrahydro-derivative of a compound of Formula I of claim1.

3. l9-ethyl-androstan-3,17-dione.

4. 19-ethyl-androsta-1,4-dien-3,17-dione.

5. l9-ethyl-androsta-1,4-dien-3-on-17-ol.

6. 19-ethyl-17-methyl-androsta-1,4-dien-3-on-17-ol.

7. A process for the preparation of a steroid of the formula wherein R Rand R are selected from the group consisting of hydrogen and loweralkyl; R; is selected from the group consisting of and wherein R isselected from the group consisting of hydrogen and lower alkanoyl,comprising the steps of (a) hydrogenating a compound of the formulawherein R through R have the meanings given above and RC, is selectedfrom the group consisting of 0 H 0R R 0 lower alkyl ll C C C R 0 loweralkenyl R 0 lower alkinyl C and C wherein R has the above meaning, toform a compound having the formula R1 R2 C it-R3 wherein R through R;have the meaning given above, and

(b) reacting the compound of Formula I with lithium and liquid ammonia.

References Cited by the Examiner 5 UNITED STATES PATENTS 3,207,7679/1965 Bowers 260-297I4 OTHER REFERENCES 15 ELBERT L. ROBERTS, ActingPrimary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 ,309,386 March 14 1967 Arthur Boller et a1.

d that error appears in the above numbered pat- It is hereby oertifieetters Patent should read as ent requiring correction and that the saidL corrected below.

line 27, for "other" read ether column 3,

Column 3, llnes 64 to 74, after the formula, insert (I) Signed andsealed this 16th day of July 1968.

(SEAL) Attest:

EDWARD J. BRENNER Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) A COMPOUND OFTHE FORMULA